1. Field of the Invention
The present invention is a method of treating various ophthalmic infections with known pharmaceutically useful oxazolidinone antibacterials.
2. Description of the Related Art
U.S. Pat. Nos. 5,164,510, 5,231,188, 5,565,571, 5,652,238, 5,688,792, 5,698,574 and 5,627,181 all disclose various oxazolidinone antibiotics which are well known to those skilled in the art.
U.S. Pat. No. 5,688,792 discloses various oxazolidinone antibiotics which can be administered orally, parenterally or topically. The topical application being by gel or cream vehicle.
Many of the presentations and posters presented at the May 11-16, 1997 at the Association for Research in Vision and Ophthalmology presented a lot of evidence that resistant microorganisms is becoming a significant problem.
Review of Ophthalmology, 94 (January 1997) discloses the use of antibacterial/antibiotic agents for ophthalmic purposes. It discloses that the xe2x80x9cbig gunxe2x80x9d of topical antibiotics is vancomycin but that it is poorly tolerated. It further disclosed that other antibacterial agents such as the two fluoroquinolones, ciprofloxacin and ofloxacin, as well as other agents such as cepharlosporins and an aminoglycoside. It appears that while the agents of choice are the fluoroquinolones that more effective agents are needed and that the fluoroquinolones have the drawback of very rapid de novo resistance development.
The Investigative Ophthalmology and Visual Science, 37(3) Abstracts 4060-B846 and 4056-B842 (1996) both disclose that while there was no resistance to ciprofloxacin in gram positive microorganisms in the late 1980""s or early 1990""s, significant resistance had developed by the mid 1990""s.
The Investigative Ophthalmology and Visual Science, 39(4) Abstract 4951-B70 and 4950-B701 (1998) both disclose problems with decreased susceptibility (increased resistance) of S. aureus because of the use of broad spectrum antibiotics in treating ophthalmic infections. This makes it more difficult for physicians to treat eye infections.
Disclosed is a method of treating an ophthalmic infection in a useful warm blooded mammal who is in need of such treatment which comprises topical administration of an ophthalmologically effective amount of an OXAZOLIDINONE.
The method of the present invention is a method of treating an ophthalmic infection in a useful warm blooded mammal who is in need of such treatment which comprises topical administration of an ophthalmologically effective amount of an OXAZOLIDINONE.
U.S. Pat. No. 5,688,792 which disclosed various oxazolidinone antibiotics disclosed they could be administered orally, parenterally or topically. There are a number of antibacterial agents which can be used topically but are much too toxic to be used ophthalmologically to treat bacterial infections of the eye.
Useful warm blooded mammals which are within the scope of the present invention include humans, pets such as dogs, cats and commercially important mammals such as horses, cattle, pigs. It is preferred that the mammal be a human, dog or cat; more preferably a human.
The OXAZOLIDINONEs of the present invention are known, see EXAMPLES 1 thru 5 (OXAZOLIDINONEs). It is preferred that the OXAZOLIDINONE be selected from the group consisting of
(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
N-((5S)-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide,
(S)-N-[[3-[5-(3-pyridyl)thiophen-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
(S)-N-[[3-[5-(4-pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride; it is more preferred that the OXAZOLIDINONE be selected from the group consisting of:
(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. It is even more preferred that the OXAZOLIDINONE be (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
Ophthalmic infections in this invention refer to inflammation of the conjunctiva (conjunctivitis) by staphylococci, streptococci and enterococci, and inflammation of the cornea (keratitis) caused by the same organisms and corneal ulcers. Bacterial conjunctivitis is the most common form of infectious conjunctivitis and bacterial keratitis accounts for 65-90% of all bacterial corneal infections.
It is preferred that the ophthalmic infection be bacterial keratitis and bacterial conjunctivitis.
The gram positive microorganisms which cause the ophthalmic infections treated by the OXAZOLIDINONEs of the present invention include Staphylococci, Streptococci, Enterococci, Bacillus, Corynebacterium, Chlamydia and Neisseria. It is preferred that the microorganism be a Staphylococci, Streptococci or Enterococci. It is more preferred that the infection be caused by Staphylococci and/or Streptococci. The important species of these genus are Staphloccus aureus, Streptococcus viridans, Staphloccus epidermidis and Streptococcus pneumoniae. The OXAZOLIDINONEs of the present invention also treat gram positive and gram negative infections caused by anaerobes such as Bacteroides fragilis. 
The ophthalmic infections are treated by administering the desired OXAZOLIDINONE(s) directly to the eye by use of a pharmaceutical formulation consisting of a solution, cream, ointment, emulsion, suspension and slow release formulations. It is preferred that the pharmaceutical formulation be a solution, cream, ointment, emulsion and suspension; it is more preferred that the ophthalmic pharmaceutical formulation be solution. It is preferred that the ophthalmologically effective amount of the OXAZOLIDINONE for treatment of ophthalmic infections is from about 0.3% to about 20%, it is more preferred that the ophthalmologically effective amount be from about 0.5% to about 18%. It is even more preferred that the ophthalmologically effective amount be from about 6% to about 16%. The OXAZOLIDINONE should be administered in the pharmaceutical formulation two thru four times daily for 7 thru 10 days or until the infection is gone. It is preferable if about 0.03 to about 2.0 ml of the ophthalmic pharmaceutical formulation containing the OXAZOLIDINONE is used each time it is administered. It is more preferable if about 0.05 (about 1 drop) to about 0.25 ml (about 5 drops) is administered.
International Publication WO96/06581 discloses a treatment fluid container having at least one opening of sufficient diameter and where the fluid is under sufficient pressure to discharge the solution as discrete jets and/or droplets. These known treatment fluid containers are useful in administering solutions containing the OXAZOLIDINONE(s). Inserts are also useful for administration of solutions of OXAZOLIDINONE(s) to the eye.
In the method of the present invention, the OXAZOLIDINONEs can be used either individually or in combination with each other. Further, they can be used in combination with other antibacterial agents. In addition, the OXAZOLIDINONEs can be used with non-antibacterial agents in treating the infections of this invention.
The exact dosage and frequency of administration depends on the particular OXAZOLIDINONE used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the OXAZOLIDINONE in the patient""s blood and/or the patient""s response to the particular condition being treated.
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
All temperatures are in degrees Centigrade.
THF refers to tetrahydrofuran.
DMF refers to dimethylformamide.
Saline refers to an aqueous saturated sodium chloride solution.
Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
Ether refers to diethyl ether.
TLC refers to thin-layer chromatography.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
OXAZOLIDINONE refers to the compounds of EXAMPLES 1 thru 5 of the present invention.